Chromosomal Syndromes and Genetic Disease Essay

When most people consider the genetic basis of disease, they might think about the rare, single gene disorders, such as cystic fibrosis (CF), phenylketonuria or haemophilia, or perhaps even cancers with a clear heritable component (for example, inherited predisposition to breast cancer). However, although genetic disorders are individually rare, they account for approximately 80% of rare disorders, of which there are several thousand. The sheer number of rare disorders means that, collectively, approximately 1 in 17 individuals are affected by them. Moreover, our genetic constitution plays a role, to a greater or lesser extent, in all disease processes, including common disorders, as a consequence of the multitude of differences in our DNA.Chromosomal Syndromes and Genetic Disease Essay  Some of these differences, alone or in combinations, might render an individual more susceptible to one disorder (for example, a type of cancer), but could render the same individual less susceptible to develop an unrelated disorder (for example, diabetes). The environment (including lifestyle) plays a significant role in many conditions (for example, diet and exercise in relation to diabetes), but our cellular and bodily responses to the environment may differ according to our DNA. The genetics of the immune system, with enormous variation across the population, determines our response to infection by pathogens. Furthermore, most cancers result from an accumulation of genetic changes that occur through the lifetime of an individual, which may be influenced by environmental factors. Clearly, understanding genetics and the genome as a whole and its variation in the human population, are integral to understanding disease processes and this understanding provides the foundation for curative therapies, beneficial treatments and preventative measures.

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With so many genetic disorders, it is impossible to include more than a few examples within this review, to illustrate the principles. For further information on specific conditions, there are a number of searchable internet resources that provide a wealth of reliable detail. These include Genetics Home Reference (https://ghr.nlm.nih.gov/), Gene Reviews (https://www.ncbi.nlm.nih.gov/books/NBK1116/), the ‘Education’ section from the National Human Genome Research Institute (https://www.genome.gov/education/) and Online Mendelian Inheritance in Man (https://www.omim.org/). In this review, an understanding and knowledge of basic principles and techniques in molecular biology, such as the structure of DNA and the PCR will be assumed, but explanations and animations of PCR (and some other processes) are available from the DNA Learning Center (https://www.dnalc.org/resources/). The focus here will be on human disease, although much of the research that defines our understanding comes from the study of animal models that share similar or related genes.Chromosomal Syndromes and Genetic Disease Essay

The human genome and variation
The human genome and the human genome reference sequence
The complete instructions for generating a human are encoded in the DNA present in our cells: the human genome, comprising roughly 3 billion bp of DNA. Scientists from across the world collaborated in the ‘Human Genome Project’ to generate the first DNA sequence of the entire human genome (published in 2001), with many additions and corrections made in the following years. Genome sequence information for humans and many other species is freely accessible through a number of portals, including the National Center for Biotechnology Information (NCBI; https://www.ncbi.nlm.nih.gov/) and Ensembl (http://www.ensembl.org/), which also provide a wealth of related information.

The majority of our DNA is present within the nucleus as chromosomes (the nuclear DNA or nuclear genome), but there is also a small amount of DNA in the mitochondria (the mtDNA or mitochondrial genome). Most individuals possess 23 pairs of chromosomes (Figure 2), therefore much of the DNA content is present in two copies, one from our mother and one from our father.Chromosomal Syndromes and Genetic Disease Essay

The human nuclear genome encodes roughly 20000 protein-coding genes, which typically consists of both protein-coding (exon) and non-coding (intron) sequences. Our genome also contains roughly 22000 genes that encode RNA molecules only; some of these RNAs form components of the translation machinery (rRNA, tRNA) but there are many more that perform various roles within the cell, including regulation of expression of other genes. In fact it is now believed that as much as 80% of our genome has biological activity that may influence structure and function. The human genome also contains over 14000 ‘pseudogenes’; these are imperfect copies of protein-coding genes that have lost the ability to code for protein. Although originally considered as evolutionary relics, there is now evidence that some may be involved in regulating their protein-coding relatives, and in fact dysregulation of pseudogene-encoded transcripts has been reported in cancer. Additionally, sequence similarity between a pseudogene and its normal counterpart may promote recombination events which inactivate the normal copy, as seen in some cases of perinatal lethal Gaucher disease. Furthermore, some pseudogenes have the potential to be harnessed in gene therapy to generate functional genes by gene editing approaches. The distribution of genes between chromosomes is not equal: chromosome 19 is particularly gene-dense, while the autosomes for which trisomy is viable (13, 18, 21) are relatively gene-poor Chromosomal Syndromes and Genetic Disease Essay

DNA and gene content of human chromosomes
Chromosome Approximate length (bp) Protein-coding genes Non-protein coding genes Pseudogenes
Note that although these numbers seem very precise they should be taken as indicative only, since (i) chromosomes of each individual will vary from the reference sequence, and (ii) the human reference genome sequence is continuously updated with corrections (the data here are from GRCh38.p12, which represents a particular ‘build’ of the human genome). Note that the data for the acrocentric chromosomes 13, 14, 15, 21, 22 does not include the shared ribosomal DNA array repeats present on the p arms (see Figure 2). Data from Ensembl, June 2018.
From the very beginning of the Human Genome Project, it was recognised that there was a huge amount of DNA sequence variation between healthy individuals, and therefore there is no such thing as a ‘normal’ human DNA sequence. However, if we are to describe changes to the DNA sequence, we need to describe these changes with respect to some baseline; this baseline is the human reference genome sequence.Chromosomal Syndromes and Genetic Disease Essay

Variation versus mutation
A geneticist’s definition of mutation is ‘any heritable change to the DNA sequence’, where heritable refers to both somatic cell division (the proliferation of cells in tissues) and germline inheritance (from parent to child). Such changes to the DNA may have no consequences but sometimes lead to observable differences in the individual (the ‘phenotype’). Consequently, in the past such alterations in the human population, particularly when they were associated with a disease state, were referred to as ‘mutations’. However, for many people this terminology has negative connotations, and brings to mind the ‘mutants’ seen in science fiction and zombie films! Therefore modern practice, particularly for medical genetics within the context of a health service, is to refer to differences from the reference sequence as ‘variants’. Variants may be further classified as benign (not associated with disease) or pathogenic (associated with disease), although there are increasing numbers of human DNA variants identified for which we are still not sure of the effect; these are termed ‘variants of uncertain significance’ or  Chromosomal Syndromes and Genetic Disease Essay

Describe how chromosomal abnormalities arise and their consequences.
Why do X linked conditions have less of an effect than autosomal
conditions?
Structure of chromosomes
The genetic information of a cell is found within the nucleus which contains
46 chromosomes; 22 pairs of autosomes and a single pair of sex
chromosomes. The ability of a cell to synthesise functional proteins relies on
the structure and the number of chromosomes. The structure of
chromosomes, which is best seen during metaphase, consists of 2 identical
sister strands known as chromatids that are attached to each other by a
centromere. The centromere consists of repetitive DNA sequences that
divide the chromosome into a short ‘p’ arm and a long ‘q’ arm. It is primarily
responsible for movement of chromosomes at cell division but the position of
the centromere is also used in chromosome classification; if the centromere
is towards the end, the chromosomes are acrocentric, if in the middle it is
metacentric whilst if the centromere is an intermediate position it is
submetacentric. At the end of each chromosome arm is a highly repeptitive
sequence of TTAGGG nucleotides which forms a structure known as the
telomere. The main function of the telomere is to prevent the ends of the
chromosome from binding to each other and also reduces chromosome
shortening during proliferation.
Chromosomal abnormalities account for a large proportion of spontaneous
pregnancy loss and childhood disability. These damaging changes usually
occur when there is an error during cell division following mitosis or meiosis
and they can be classed into two main groups; structural and numerical.Chromosomal Syndromes and Genetic Disease Essay
Numerical abnormalities
The gain or a loss of one or more chromosomes in a cell results in aneuploidy
and can lead to a wide variety of disorders depending on the chromosome
affected. The main cause of aneuploidy is nondisjunction where there is a
failure of the chromosome pairs to separate during anaphase of either
meisosis 1 or 2. Nondisjunction in meisosis 1 leads to the formation of a
gamete with 2 homologs of one chromosome pair, whereas nondisjunction in
meisos 2 results in the gamete containing 2 copies of one homologos of the
chromosome pair. The occurrence of nondisjunction in oocytes and the
diseases associated with it increase with maternal age.
Monosomy occurs in fertilised gametes that are missing a single
chromosome. This can be due to a gamete with an absence of a specific
Bavidra kulendrarajah
chromosome as a result of nondisjucntion fusing with a gamete that contains
a single copy of the chromosome. One example of monosomy includes the
Turner syndrome which is due to the absence of an X chromosome.
Symptoms often include a webbed neck, widely spaced nipples, short stature
and a wide carrying angle. Another diagnostic sign of turner syndrome is
primary amenorrhoea and infertility.
In comparison trisomy is due to the presence of an extra chromosome in
fused gametes. This occurs when a gamete with 2 copies of the chromosome
due to nondisjunction fuses with a chromosome with only one copy of the
chromosome. A well known trisomy that doesn’t lead to spontaneous
abortion is Down’s syndrome where the cells have 3 copies of chromosome
21 and the occurance of this disease is 1 in 700. In the majority of patients
Down’s syndrome was due to the failure of separation of the pair of
chromosomes during anaphase of maternal meiosis 1. Symptoms that are
associated with having this disorder include mental retardation, severe
hypotonia, thyroid problems and congenital cardiovascular defects. Similarly
Patau syndrome is due to trisomy 13 and the occurance rate is 1 in every
5000. Children with Patau syndrome often suffer from clefting, finger and toe
abnormalities, severe mental abnormalities and heart and scalp defects. The
last type of viable trisomy is trisomy 18 which similarly also causes severe
mental retardation but the most characteristic sign is rocker bottom feet and
clenched fingers. Patients with trisomies can be rapidly diagnosed using
fluorescent in-situ hybridisation where radioactively labelled specific
centromeric probes are used to bind with their complementary target
sequences. If trisomies are present, when the chromosomes are viewed
under a fluorescent microscope there will be three highlighted regions
indicating three chromosomes of the same type.
Structural abnormalities
The second main class of chromosomal abnormalities are structural
abnormalities which include translocations, deletions, insertations,
inversions, rings and isochromosomes.
a) Translocations
In translocations there is a transfer of genetic
material form one chromosome to another and
there are two types. Reciprocal translocations
occur when breaks occur in 2 chromosomes
and the two segments detached are
exchanged to form new derivatives Chromosomal Syndromes and Genetic Disease Essay

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A genetic disorder is a disease that is caused by an abnormality in an individual’s DNA. Abnormalities can range from a small mutation in a single gene to the addition or subtraction of an entire chromosome or set of chromosomes” (Letsou). Most individuals are either related to or know someone who is effected by some type of disability. Many of these disabilities are caused by genetic disorders. Genetic disorders may alter physical appearance and cause mild to severe mental retardation. Fragile X syndrome, Down syndrome, Turners syndrome and many other syndromes result from a mutation of a chromosome, an extra chromosome, or too few chromosomes.
Discovered in 1991, Fragile X syndrome is considered a fairly new genetic disorder. According…show more content…
Unlike many other syndromes those affected by Fragile X are expected to have an average life span and have fewer health problems. Down syndrome, also known as trisomy 21, or trisomy G is one syndrome that has many characteristics. In 1866 “English doctor, John Langdon Down published a description of the condition” (Downs Syndrome Association).Chromosomal Syndromes and Genetic Disease Essay  According to Genetics Home Reference, Down syndrome is a chromosomal condition that is associated with intellectual disability, a characteristic facial appearance, and weak muscle tone in infancy. Down syndrome is caused by an extra copy of the 21st chromosome. Unlike Fragile X syndrome, Down syndrome is most commonly detected by the appearance of the individual. Approximately 15% of people with Down syndrome “have an underactive thyroid gland. The thyroid gland is a butterfly-shaped organ in the lower neck that produces hormones. Some of the problems these individuals may have are heart defects Chromosomal Syndromes and Genetic Disease Essay